The invention relates to the use of a LTB4 antagonist or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment and/or prevention of diseases caused by increased expression of mucin genes in the bronchial or gastrointestinal epithelium.
Cystic fibrosis (CF) is an inherited disease primarily due to a defect in the cystic fibrosis trans-membrane regulating protein (CFTR). This results in abnormal chloride transfer across epithelial membranes. Symptoms appear in a number of organ systems, but for most patients the most important pathological changes associated with the CFTR defect are those in the lung. Patients with cystic fibrosis produce excessive quantities of viscous mucus which readily becomes infected. Recurring infections are associated with worsening of the condition of the patient and an increased high risk of death. Exactly how the CFTR defect causes increased mucus production is not known. One hypothesis is that the CFTR mutation causes changes in the tracheal epithelium which engender chronic bacterial infection, particularly with Pseudomonas aeruginosa. These bacteria stimulate expression of mucin genes, such as MUC-2 and MUC-5. Overproduction of mucus, combined with mucus dehydration related to the underlying chloride channel defect, lead to formation of mucus plugs and eventually to lung failure (J. D. Li, A. F. Dohrman, M. Gallup et al., Transcriptional Activation of Mucin by Pseudomonas aeruginosa Lipopolysaccharide in the Pathogenesis of Cystic Fibrosis Lung Disease, Proc. Natl. Acad. Sci. U.S.A., 1997, 94:967-972; A. Dohrman, S. Miyata, M. Gallup et al., Mucin Gene (MUC 2 and MUC 5AC) Upregulation by Gram-positive and Gram-Negative Bacteria, Biochim. Biophys. Acta, 1998, 1406:251-259).
Cystic fibrosis is associated with markedly elevated levels of leukotriene B4 in the epithelial lining fluid of the lung (M. W. Konstan, R. W. Walenga, K. A. Hilliard, J. B. Hilliard, Leukotriene B4 Markedly Elevated in the Epithelial Lining Fluid of Patients with Cystic Fibrosis, Am. Rev. Respir. Dis., 1993, 148:896-901), and this elevation is also detectable in the sputum (J. T. Zakrzewski, N. C. Barnes, P. J. Piper, J. F. Costello, Detection of Sputum Eicosanoids in Cystic Fibrosis and in Normal Saliva by Bioassay and Radioimmunoassay, Br. J. Clin. Pharmacol., 1987, 23:19-27). The source of this LTB4 is unclear since both inflammatory cells such as neutrophils which are much more abundant in the CF lung as well as epithelial cells have the necessary enzyme machinery to synthesize this leukotriene.
Similarly, the exact mechanism by which Pseudomonas aeruginosa stimulates the increased expression of mucin genes in the bronchial epithelium is also unclear. Certainly, both clinically and experimentally, infection with Pseudomonas aeruginosa is associated with neutrophil infiltration into the lung, and products of activated neutrophils such as elastase, TGFbeta and TNFalpha are known to be able to increase the amount of mucin specific RNA in the bronchial epithelium either by stimulating the transcription of the genes or by impeding RNA degradation (K. Takeyama, C. Agusti, I. Ueki, J. Lausier, L. O. Cardell, J. A. Nadel, Neutrophil-Dependent Goblet Cell Degranulation: Role of Membrane-Bound Elastase and Adhesion Molecules, Am. J. Physiol. 1998, 275:L294-L302; K. Takeyama, K. Dabbagh, H. M. Lee et al., Epidermal Growth Factor System Regulates Mucin Production in Airways, Proc. Natl. Acad. Sci. U.S.A., 1999, 96:3081-3086). However, there are also direct effects of Pseudomonas aeruginosa on pulmonary epithelial cells, via bacterial lipopolysaccharides (J. D. Li, A. F. Dohrman, M. Gallup et al., 1997; loc. cit.), via bacterial proteases (J. D. Klinger, B. Tandler, C. M. Liedtke, T. F. Boat, Proteinases of Pseudomonas aeruginosa Evoke Mucin Release by Tracheal Epithelium, J. Clin. Invest., 1984, 74:1669-1678), or via bacterial adhesins (J. K. Ichikawa, A. Norris, M. G. Bangera et al., Interaction of Pseudomonas aeruginosa with Epithelial Cells: Identification of Differentially Regulated Genes by Expression Microarray Analysis of Human cDNAs, Proc. Natl. Acad. Sci. U.S.A., 2000; 97:9659-9664). The role of LTB4 in both the neutrophil-mediated and the direct effects of Pseudomonas aeruginosa on the pulmonary epithelium is unknown.
The present invention relates to the use of an LTB4 antagonist of formula (I), 
a tautomer thereof or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment and/or prevention of diseases caused by increased expression of mucin genes in the bronchial or gastrointestinal epithelium, in particular diseases caused by Pseudomonas aeruginosa such as cystic fibrosis.
Another aspect of the invention is a method for the treatment of patients suffering from diseases caused by increased expression of mucin genes in the bronchial or gastrointestinal epithelium which method comprises administering to the patient in need thereof an effective amount of a compound of formula (I), a tautomer thereof or a pharmaceutically acceptable salt thereof.
The invention further provides a medicament containing, separately or together,
(A) a compound of formula (I), a tautomer thereof or a pharmaceutically acceptable salt thereof;
(B) one or more additional active ingredients selected from the group consisting of antibiotics, LTA4 hydrolase inhibitors, 5-lipoxygenase inhibitors and agents that enhance mucus clearance; and
(C) optionally a pharmaceutically acceptable carrier,
for simultaneous, sequential or separate administration in the treatment of diseases caused by increased expression of mucin genes in the bronchial or gastrointestinal epithelium.
Furthermore, the invention relates to a pharmaceutical kit comprising at least two separate unit dosage forms (A) and (B):
(A) one of which comprises a composition containing a compound of formula (I), a tautomer thereof or a pharmaceutically acceptable salt thereof and optionally a pharmaceutically acceptable carrier;
(B) one of which comprises a composition containing one or more additional active ingredients selected from the group consisting of antibiotics, LTA4 hydrolase inhibitors, 5-lipoxygenase inhibitors and agents that enhance mucus clearance and optionally a pharmaceutically acceptable carrier.